Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stem cell factor (SCF) promotes the growth of multilineage hematopoietic cells. SCF is a product of the steel (Sl) locus of the mouse, and it is a ligand for the c-kit proto-oncogene receptor. Previous studies have investigated the distribution of SCF mRNA in developing and adult tissues of the rat, including the brain. However, there have been conflicting reports on the distribution of SCF mRNA in adult rat brain. Specially noteworthy was one report of the absence of SCF mRNA in adult hippocampus, while another group reported the presence of that mRNA in the dentate gyrus of the hippocampus. We conducted this study to determine the precise localization of SCF mRNA in adult brain, and were especially interested in determining whether that mRNA is localized in adult hippocampus. We used in situ hybridization histochemistry to demonstrate that the gene encoding SCF is actively expressed in neuron-like cells in various regions of adult rat brain. Our data show that SCF mRNA is present in neuron-like cells in the thalamus, cerebral cortex, cerebellum, and hippocampus, particularly in the dentate gyrus, but also in CA1, CA2, and CA3. We did not localize SCF mRNA in glia-like cells. Dyskeratosis congenita is a severe human disorder, associated with dyskeratosis, anemia, and mental retardation. It has been postulated that dyskeratosis congenita is due to a deficiency in SCF function. It is unknown why patients with dyskeratosis congenita suffer from mental retardation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Localization of stem cell factor mRNA in adult rat hippocampus. 748 32

The binding of the muscarinic acetylcholine antagonist quinuclinidylbensilate to its specific receptors was measured by quantitative autoradiography in the brain of the HPH-5 mouse, a phenylalanine hydroxylase-deficient mouse mutant, as a model for human PKU. Three types of response to a hyperphenylalaninemic condition were observed: no effect as in the putamen; a gradual decrease over time such as in several areas of the cerebral cortex and the hippocampus; a transient increase, followed by a decrease, such as in the frontal area of the cerebral cortex. Of particular significance is the effect on the CA1 and CA3 layer of the hippocampus, since this structure has been implicated in the acquisition and storage of long-term memory. Hyperphenylalaninemia leads to a decrease in neurotransmitter receptor density and, therefore, to a decrease in connectivity, which may form the basis for the mental retardation in this condition.
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PMID:Loss of neurotransmitter receptors by hyperphenylalaninemia in the HPH-5 mouse brain. 776 46

Previous studies on the effect of hyperphenylalaninaemia on the development of the muscarinic acetylcholine receptor in the cerebrum of the rat, using alpha-methylphenylalanine-induced hyperphenylalaninaemia, have shown a gradual and steady decrease in the number of binding sites for this neurotransmitter. The HPH-5 mouse, a phenylalanine hydroxylase mutant, can be hyperphenylalaninaemic without the use of a hydroxylase inhibitor. By employing quantitative autoradiography using [3H]quinuclinidylbenzilate to label muscarinic acetylcholine receptors, a refined analysis of this decrease in neurotransmitter binding sites can be made. The decrease was confirmed and is therefore due to the hyperphenylalaninaemia per se and not to the use of the inhibitor. Various areas of the brain reacted differently to hyperphenylalaninaemia, from no change (putamen) to a gradual decrease (external layer of the olfactory bulb, parietal, occipital and cingulate areas of the cerebral cortex, CA1 and CA3 layer of the hippocampus) to a decrease preceded by a transient increase (frontal area of the cerebral cortex, caudate nucleus). The extent of these changes depends on the duration of exposure to hyperphenylalaninaemia as well as on the degree of brain maturation, but can even be observed in the brain of the adult mouse on a hyperphenylalaninaemic regimen for 11 days. Since the hippocampus has been shown to be involved in the long-term storage of information, damage to this structure by hyperphenylalaninaemia may provide a clue to the global mental retardation observed in untreated PKU.
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PMID:The effect of hyperphenylalaninaemia on the muscarinic acetylcholine receptor in the HPH-5 mouse brain. 812 72

The amino acid proline has long been suspected to serve as a modulator of synaptic transmission in the mammalian brain, but no such function has been identified. The selective expression of high affinity proline transport by a subset of glutamate pathways suggested that proline might play a role in synaptic transmission at these sites. This idea was tested with use of one such pathway, the Schaffer collateral-commissural projection to CA1 pyramidal cells of the rat hippocampus. Proline enhanced the initial slope of the field EPSP without affecting axonal excitability or the magnitude of paired-pulse facilitation. Proline-induced potentiation far outlasted the period of proline application and required the activation of NMDA receptors. Proline enhanced Schaffer collateral-commissural synaptic transmission even when the connections between areas CA1 and CA3 had been interrupted. Potentiation was observed with a proline concentration normally present in human CSF (3 microM). A concentration typical of CSF in persons with the genetic disorder hyperprolinemia type II (30 microM) produced a somewhat greater effect. Occlusion experiments suggested that proline-induced potentiation and tetanus-induced long-term potentiation utilize largely distinct transduction mechanisms. Proline-induced potentiation could be blocked by a prior high frequency stimulus, whether or not the stimulus evoked long-term potentiation. These results suggest that endogenous extracellular proline regulates the basal function of some glutamate synapses by maintaining them in a partially potentiated state. They may also facilitate understanding of the seizures and/or mental retardation associated with genetic disorders of proline metabolism.
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PMID:Proline-induced potentiation of glutamate transmission. 925 26

Entorhinal cortex (EC), fascia dentata (FD), hippocampus (HP), and basal ganglia (BG) were studied in Rett syndrome (RS) cases and compared with control brains and an autism case. Kluver-Barrera and Golgi methods were used. In RS most of the areas of EC, HP, and FD showed severe cell hypochromia. In the EC all cells of layer II and most in layer III were in a state of total chromatolysis or were "ghost" cells, but the cells of layers V and VI were preserved and moderately hyperchromic. In FD and HP the majority of the granular cells and cells of CA3 and CA4 fields were severely hypochromic, whereas in the CA1 field most cells were normal or slightly hypercaryochromic. In BG mostly mild or moderate aberration from normal cell structure was observed: in striatum, mild hypercaryochromia of small neurons and more expressive hyperchromia of large neurons were found; and in pallidum, mild or moderate hypercaryochromia to severe hyperchromia in pallidum internum was found. Degeneration of thick myelinated fibers was evident in pallidum. Large striatal and pallidal neurons showed signs of constructive changes in Golgi slices. These data allow the determination of the cause of the main symptoms of RS. The motor disorders, including specific stereotyped movements, could be related to the enhanced activity of BG cells due to their deafferentation from the side of the neocortex and to supposed hyperactivity of the EC-striatal pathway; the mental retardation and epileptic seizures could be due to FD-HP involvement.
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PMID:Morphological study of the entorhinal cortex, hippocampal formation, and basal ganglia in Rett syndrome patients. 1034 23

Maternal alcoholism and thiamine deficiency are frequently considered to be the causal agents of the central nervous system (CNS) damage associated with mental retardation in the offspring. For further understanding of pathological mechanisms underlying CNS damage in both disorders, histological studies were undertaken in developing rats to compare the hippocampus CA3 pyramidal cells measurements and density between three patterns of thiamine deficiency and chronic alcohol exposure. Female rats were given thiamine-deficient diet during different periods of gestation and lactation to obtain pre-, peri-, and postnatal thiamine-deficient pups. Twelve percent ethanol/water drinking fluid was given to mothers throughout gestation and lactation to obtain ethanol-exposed pups. Thiamine was administered during developmental ethanol exposure to assess the extent of interference between ethanol and thiamine metabolism. Nondrug-treated dams were allowed ad lib access to food and water during gestation and lactation to yield control pups. Hippocampus histology was performed in 45-day-old rats, and the CA3 pyramidal cells measurements and density assessed and compared between all treatment groups. It appears that the mean nuclear size of pyramidal cells in the field CA3 was significantly reduced in all the treatments compared to the control. While the mean nuclear size decreased more severely in development ethanol exposure than in the three patterns of thiamine deficiency, no significant difference was noted when pre-, peri-, and postnatal thiamine-deficient rats were compared. However, thiamine administration during developmental ethanol exposure partially restored the mean nuclear size. In contrast, comparisons between ethanol-exposed pups and the three patterns of thiamine-deficient pups, exhibited similar intensity in the deficit of CA3 pyramidal cells. Cell loss generated by ethanol treatment was not suppressed by thiamine administration. Common and separate mechanisms underlying the effects of alcohol intoxication and thiamine deficiency on cell death and cell atrophy were suggested.
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PMID:Comparative effects of developmental thiamine deficiencies and ethanol exposure on the morphometry of the CA3 pyramidal cells. 1049 92

Down Syndrome (DS) is a major cause of mental retardation and is associated with characteristic well-defined although subtle brain abnormalities, many of which arise after birth, with particular defects in the cortex, hippocampus and cerebellum. The neural cell adhesion molecule DSCAM (Down syndrome cell adhesion molecule) maps to 21q22.2-->q22.3, a region associated with DS mental retardation, and is expressed largely in the neurons of the central and peripheral nervous systems during development. In order to evaluate the contribution of DSCAM to postnatal morphogenetic and cognitive processes, we have analyzed the expression of the mouse DSCAM homolog, Dscam, in the adult mouse brain from 1 through 21 months of age. We have found that Dscam is widely expressed in the brain throughout adult life, with strongest levels in the cortex, the mitral and granular layers of the olfactory bulb, the granule cells of the dentate gyrus and the pyramidal cells of the CA1, CA2 and CA3 regions, the ventroposterior lateral nuclei of the thalamus, and in the Purkinje cells of the cerebellum. Dscam is also expressed ventrally in the adult spinal cord. Given the homology of DSCAM to cell adhesion molecules involved in development and synaptic plasticity, and its demonstrated role in axon guidance, we propose that DSCAM overexpression contributes not only to the structural defects seen in these regions of the DS brain, but also to the defects of learning and memory seen in adults with DS.
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PMID:Down syndrome cell adhesion molecule is conserved in mouse and highly expressed in the adult mouse brain. 1185 73

The fragile-X mental retardation protein (FMRP) is greatly reduced or absent in individuals with fragile-X mental retardation syndrome, a common, heritable form of mental retardation. Morphological studies suggest that this protein functions in normal synapse maturation and neuronal plasticity. Examination of human brain autopsy tissue has shown that fragile-X patients exhibit long, thin spines more frequently, and stubby mushroom-shaped spines less frequently, than these two types of spines are seen in normal autopsy tissue. Fragile-X tissue also has a greater density of these spines along dendrites, which suggests a possible failure of synapse elimination. Fmr1 knockout mice and wild-type littermates brains were processed for Timm staining, which reveals the zinc-rich terminals of the dentate gyrus, the mossy fibers. The Fmr1 knockout mice exhibited a pattern of Timm granule-staining within the stratum oriens of subfield CA3 and the inner molecular layer that was significantly different than staining seen in wild-type animals. The sources and consequences of the altered terminal staining are unclear, but are discussed in relation to immature synapse morphology, a failure of normal regression of synapses, and a potential biological penalty of such a failure to regress.
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PMID:Altered mossy fiber distributions in adult Fmr1 (FVB) knockout mice. 1191 88

Duchenne muscular dystrophy is characterized by a defect in dystrophin, which often causes mental retardation in addition to progressive muscular weakness. As dystrophin is localized in synaptic regions of the CNS, cognitive abnormalities associated with Duchenne muscular dystrophy are attributable to synaptic dysfunction. We report that dystrophin-deficient mdx mice were more resistant to kainic acid-induced seizures but not to GABA antagonist-induced seizures compared with the control mice. The kainic-acid receptor density in the brain was significantly lower in the mdx than in the control, although the density of muscarinic cholinergic receptors, another important neurotransmitter receptor for cognitive function, was normal. Moreover, mdx had significantly lower Timm staining intensity in the mossy fibers, which originate from the dentate granule cells and terminate on the pyramidal cells in the CA3 of the hippocampus. These results suggest that an instability of neurotransmitter receptors, such as kainate-type glutamate receptors, on synaptic membranes due to the disruption of dystrophin complex induces inefficient neurotransmission in Duchenne muscular dystrophy patients.
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PMID:Abnormal kainic acid receptor density and reduced seizure susceptibility in dystrophin-deficient mdx mice. 1261 79

Mental retardation represents the more invalidating pathological aspect of Down syndrome, DS, and has a hard impact in public health. Modifications in DS brain, concerning abnormal size, neuronal differentiation, and cell density, cause changes in the neurophysiology and behavior of DS patients, and could be determined by dosage imbalance of genes localized in the DS critical region, DCR. Among these genes, C21orf5 showed high homology with Caenorhabditis elegans Pad1 involved in cellular differentiation and patterning. To shed light on C21orf5 role in DS, we performed molecular characterization of human and mouse orthologs, their spatio-temporal expression during development and in adult, and overexpression in DS and transgenic mice. C21orf5 was widely expressed early in embryogenesis in the nervous system. Later, its expression became differential and increased in mesencephalon and rhomboencephalon. This developmental expression profile evolves selectively in adult brain with higher signals in hippocampus, cerebellum, perirhinal, and entorhinal cortex, compared to the other cortical regions. Cellular specificity was detected in hippocampus with higher C21orf5 mRNA level in CA3 cells. Our findings appoint C21orf5 as candidate gene for mental retardation: Its overexpression in DS cells may contribute to gene imbalance in DS.Its specific expression in normal and its mirroring pattern in transgenic mice correspond to abnormal regions in DS patients and to neurological phenotype of transgenic mice. Altered cortical lamination in transgenic mice and the Pad1 ortholog function suggest a potential role of C21orf5 in cell differentiation. Its patterned differential expression in the medial temporal-lobe system, including hippocampal formation and perirhinal cortex involved in memory storage, and learning and memory defects in the transgenic mice suggest a specialized role for C21orf5 in cognitive processes. These evidences suggest that C21orf5 is an attractive candidate gene contributing to neurological alterations responsible for mental retardation in DS patients.
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PMID:The differentially expressed C21orf5 gene in the medial temporal-lobe system could play a role in mental retardation in Down syndrome and transgenic mice. 1276 18


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